This article includes discussion of globoid cell leukodystrophy, galactosylceramide lipidosis, and Krabbe disease. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Globoid cell leukodystrophy, or Krabbe disease, is an autosomal recessive, rapidly progressive fatal disease when it occurs in infancy. The disease usually begins between the ages of 3 and 6 months with ambiguous symptoms, such as irritability or hypersensitivity to external stimuli, but soon progresses to severe mental and motor decline. Patients are initially hypertonic with hyperactive reflexes, but they later become flaccid and hypotonic. Blindness and deafness are common. Patients with late-onset forms, including adult onset, may present with blindness, spastic paraparesis, and dementia. Saposin A deficiency is a rare cause of Krabbe disease. Brain MRI has characteristic features that depend on the age of onset of the disease (infantile, juvenile, or adult). Optic nerve and cauda equina enlargement and enhancement is common, as well as midbrain atrophy. The presence of peripheral nerve enlargement detected by ultrasound strongly supports the diagnostic possibility of Krabbe disease (52). Newborn screening and presymptomatic hematopoietic stem cell transplantation have not yielded clear benefits.
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• Globoid cell leukodystrophy may occur at any age, but the infantile type is the most common.
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• Typical MRI changes that vary according to each phenotype suggest the diagnosis.
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• The adult onset type is the most prevalent in certain populations such as Japan.
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• Hematopoietic stem cell transplantation in presymptomatic infants only mitigates the disease and is not the optimal therapy it was once hoped to be.
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• Measuring psychosine, a major offending metabolite in Krabbe disease, in dried blood spots helps in diagnosis and in differentiating infantile from later onset variants, as well as in monitoring disease progression and response to treatment.
Historical note and terminology
Globoid cell leukodystrophy, or Krabbe disease, was described in 1916. Krabbe reported the clinical and neuropathologic description of 5 cases that appeared to represent a new disease entity (49). Previous neuropathologic studies, however, had described the "diffuse gliosis" of brain that was later characterized as "diffuse brain-sclerosis" in Krabbe patients (11; 09). Collier and Greenfield in 1924 used the term "globoid cells" to describe the phagocytic cells that appeared unique to this disorder (20). Hallervorden suggested that these globoid cells may contain kerasin or cerebroside (34). Biochemical and histochemical studies confirmed the presence of cerebroside in globoid cells (10; 05), and galactocerebroside was the only glycolipid that could produce globoid cells when injected into the central nervous system of experimental animals (03). Analytical biochemical studies of total brain lipids did not show an increase in galactosylcerebroside in this disease, but rather a lowering of total cerebroside and sulfatide and a reduced sulfatide-to-cerebroside ratio (86). Only a fraction of brain lipids enriched in the specialized globoid cells showed an increase in galactosylceramide (05). In 1970, Malone reported a deficiency of leukocyte galactosylceramide beta-galactosidase in a Krabbe disease patient (62); this was confirmed by Suzuki and Suzuki, who demonstrated the enzyme deficiency in the brain, liver, and spleen of 3 Krabbe disease patients (85). Psychosine, a related glycolipid, was suggested to be the toxic metabolite responsible for the pathogenesis of this disorder (65; 83). The gene for the galactosylceramidase (GALC) enzyme has been mapped to chromosome 14 (102), and the cDNA has been cloned by Chen and associates (16).